In contrast to large, multinational, industry sponsored clinical trials, far lower sustained virological responses (SVR) to standard of care (SOC) pegylated interferon (IFN) plus ribavirin therapy have been observed in urban clinics and in developing countries such as Brazil, where ethnicity and host factors affect the outcome of treatment. For example, induction of a small group of IFN stimulated genes (ISGs) has been shown to predict response to therapy, while genetic variation in the interleukin 28B gene predicts treatment-induced and spontaneous viral clearance and may explain why African Americans and minorities respond poorly to therapy. Thus, it is imperative to understand how IFN-based therapy works in different populations and ethnic backgrounds so as to minimize improper use of new Specifically Targeted Antiviral Therapy for HCV (STAT-C) therapies and the subsequent emergence of resistant viruses. To address this issue, we have begun a clinical trial in Brazil driven by the hypothesis that host genetics and innate antiviral responses shape the outcome of antiviral therapy. We will measure hepatic gene expression, host genetic polymorphisms, and viral kinetics, and correlate these host and viral factors with outcome of therapy. The proposed study will provide the first detailed description of IFN responses in Brazilian patients, who represent a diverse ethnic population. It will also compare the South American experience with European and North American-based clinical trials, and will delineate how SOC therapy affects host innate responses that ultimately control HCV infection. Finally, the proposed studies may lead to improved therapeutic strategies that will enhance global control of HCV by reducing the spread of resistant strains.